Kidney Week

Abstract: SA-OR86

Molecular Pathways Associated with Early Vascular Calcification in Pediatric CKD

Session Information

• Pediatric Nephrology: Clinical and Genetic Studies
  November 04, 2023 | Location: Room 105, Pennsylvania Convention Center
  Abstract Time: 05:42 PM - 05:51 PM

Category: Pediatric Nephrology

• 1900 Pediatric Nephrology

Authors

• Bernardor, Julie, CHU de Nice, Nice, France

Julie Bernardor, DrMed, MSc

• Bartosova, Maria, Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany

Maria Bartosova,

• Zhang, Conghui, Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany

Conghui Zhang,

• Marinovic, Iva, Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany

Iva Marinovic,

• Herzog, Rebecca, Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Vienna, Austria

Rebecca Herzog,

• Kratochwill, Klaus, Christian Doppler Laboratory for Molecular Stress Research in Peritoneal Dialysis, Department of Pediatrics and Adolescent Medicine, Vienna, Austria

Klaus Kratochwill,

• Farlay, Delphine, INSERM UMR 1033, Lyon, Auvergne-Rhônes-Alpes, France

Delphine Farlay,

• Dijkgraaf, Ingrid, Universiteit Maastricht, Maastricht, Limburg, Netherlands

Ingrid Dijkgraaf,

• Jaminon, Armand, Universiteit Maastricht, Maastricht, Limburg, Netherlands

Armand Jaminon,

• Schurgers, Leon J., Universiteit Maastricht, Maastricht, Limburg, Netherlands

Leon J. Schurgers,

• Schmitt, Claus Peter, Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany

Claus Peter Schmitt,

Background

Children with advanced stages of chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) and vascular calcification (VC) may already occur during childhood. This study comprehensively investigated the molecular pathways underlying early VC in children with CKD stage 5.

Methods

Arterioles from children with normal renal function and CKD5, (median age 8.9 and 8.8 years) were analyzed using digital quantitative histomorphometry, von Kossa staining and ¹⁸F-sodium autoradiography (¹⁸F-NaF) for calcium deposit quantification. Arteriolar transcriptome and proteome analyses were followed by gene set enrichment (GSEA) and Ingenuity pathway analysis. Based on literature mining, a VC pathway library was established consisting of 442 biological processes and molecular functions and associated genes were extracted from Gene Ontology database. The identified key molecular mechanisms were validated in independent pediatric CKD5 cohorts (n=32) and healthy controls (n=20) using quantitative immunostaining.

Results

Von Kossa staining did not reveal calcium deposits, but ¹⁸F-NaF autoradiography demonstrated arteriolar microcalcifications in children with CKD5. Compared to children with normal renal function, the arteriolar lumen/vessel ratio was reduced (p=0.001), due to intima and media thickening (p<0.0001/0.02), together with CD68+ macrophage infiltration in the subendothelial space (p=0.001/0.02). Multi-omics VC pathway analysis identified 30 pathways primarily associated with actin cytoskeleton, Wnt signaling, extracellular matrix (ECM) organization, complement activation, apoptosis, and ossification regulation. In independent age-matched cohorts, two components of the Wnt pathway, DKK3 and Wnt2b, were decreased (p=0.0004/0.009). Fibronectin-1, a major regulator of ECM, was identified as a hub gene in VC and showed reduced abundance in children with CKD5 (p=0.001). Arteriolar osteoglycin, involved in ectopic bone formation, was increased in CKD5 (p<0.001).

Conclusion

Arteriolar microcalcifications are already present in young children with CKD5. We provide a comprehensive analysis of underlying molecular pathways and identified processes involved in vascular remodeling which open new avenues for potential therapeutic targets.